Analysis Tools
homeostasis/metabolism
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• polysome profiling of brain cortical lysates showed a significant shift of ribosomes from actively translating polysomes toward the monosomal fraction, indicating decreased mRNA translation initiation in the brain
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• after birth (P2-P14) and in adult stages (>P40), brain levels of branched-chain amino acids (BCAAs), esp. leucine and isoleucine, are abnormally low while levels of a few other amino acids (e.g., histidine, serine, and phenylalanine) are increased relative to those in age-matched controls
• brain histidine levels are several fold higher than in control mice
• brain levels of leucine and isoleucine are normalized after 3 weeks of intracerebroventricular (i.c.v.) BCAA (leucine and isoleucine) delivery
• brain levels of several other large neutral amino acids (LNAAs) including tyrosine and tryptophan are relatively normal, and serum amino acid levels are unchanged
• no major changes in brain LNAA and BCAA levels are noted at E14.5
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• brain levels of phenylalanine are increased
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• brain serine levels are modestly but significantly increased
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• mice show abnormal activation of the amino acid response (AAR) signal transduction pathway in the brain
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behavior/neurological
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• at P55-P65, mice exhibit motor delay and autism-like phenotypes
• some neurobehavioral phenotypes can be rescued by i.c.v. administration of leucine and isoleucine in adulthood
• mice do not show excessive grooming or stereotyped behavior in the marble burying test
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• 89% of mice display hind limb clasping
• fewer mice (50%) show clasping after 3 weeks of i.c.v. BCAA delivery
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• mice show increased latency to cross the beam in the walking beam test
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• in the footprint test, mice show decreased stride and stance length and increased sway length relative to controls
• gait is improved after 3 weeks of i.c.v. BCAA delivery with complete normalization of the sway length
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• rearing is significantly reduced
• number of rearings is normalized after 3 weeks of i.c.v. BCAA delivery
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• mice show reduced explorative behavior and lower velocity in an open field test
• open field activity is normalized after 3 weeks of i.c.v. BCAA delivery
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• in the three chamber sociability test, P55-P65 mice fail to show preference for an unfamiliar caged wild-type mouse over a caged object, unlike controls
• in the juvenile social interaction test, P25-P35 mice tend to stay farther apart from their cage mate and show fewer nose-to-nose contacts than controls
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• in the isolation-induced ultrasonic vocalization test, pups separated from the mother emit an increased number of calls starting at P8
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• at P55-P65, mice exhibit motor delay
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skeleton
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• 44% of mice display kyphosis
• fewer mice (25%) show kyphosis after 3 weeks of i.c.v. BCAA delivery
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nervous system
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• brain neurotransmitter levels (dopamine, serotonin, histamine) are normal
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• EM imaging of somatosensory cortex layers 2-3 revealed a decreased area of GABAergic boutons and decreased density of vesicles per bouton
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• the intensity of vesicular GABA transporter (VGAT) staining, a marker for GABAergic presynaptic terminals, is reduced in the somatosensory cortex
• however, protein levels the GABAergic postsynaptic marker neuroligin 2 are normal
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• mice show a significant reduction of vesicle number in symmetric synapses in the somatosensory cortex
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• mice show a significant reduction of vesicle number in symmetric synapses in the somatosensory cortex
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• mice exhibit a significant cortical excitation and inhibition imbalance
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• mice show a slight increase in the amplitude of mEPSCs in somatosensory cortex layers 2-3 pyramidal neurons
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• mice show a marked reduction in the frequency of mIPSCs in somatosensory cortex layers 2-3 pyramidal neurons as well as in cerebellar Purkinje cells
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cellular
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• polysome profiling of brain cortical lysates showed a significant shift of ribosomes from actively translating polysomes toward the monosomal fraction, indicating decreased mRNA translation initiation in the brain
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| autism spectrum disorder | DOID:0060041 | J:238065 | ||
